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T1D, T2D, and MODY

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Supplementary materials Supplementary Table 1. The most significant obesity genes that are common between the different types of diabetes; T1D, T2D, and MODY. Genes Genes Genes Genes VDR BDNF PPARGC1A SERPINC1 ACE IFNG SERPINE1 APOA1 HMGCR ABCA1 CYP19A1 CCK MMP2 RETN VCAM1 ADRB2 EDN1 IL4 TP53 GAPDH ABCB7 BCHE TNF APC GSR BCL2 INSR TLR2 FASLG TNFRSF11B IFNA1 VEGFA GGT1 CD36 HNF1B CDKN2A CYBA FGF2 GNRH1 TGFB1 IGF1 CLU HLA-DRB1 KCNJ11 CCL11 PCK2 IL1A TFRC PTEN HK2 LDLR ABCC8 HMOX1 G6PD LPL GAST HNF1A TF CAT TSHR NOS2 GCK MPO JUN INS IGF1R TCF7L2 HCRT FLT1 IRS1 LIPC SERPINF2 SLC6A4 GHRL SELP TIMP1 SOD2 ICAM1 GCG CSF2 BGLAP RECK F5 GHRH MMP3 RPS27A IL8 MMP9 PPARA TNFRSF1B HLA-A CD14 NGF APOB SLC2A2 ADIPOQ GATA3 CS AKT1 IL2RA LTF PIK3R1 PAX4 IL5 GRP TTR AGT NR1H2 LEP CGA TNFRSF1A PTPRN2 PPARG STAT3 OXT HNF4A SPP1 CYP1A2 CRP F2 TG HIF1A PTGS2 CYP2C19 CALCA AHSG NOS1 SERPINA1 B2M CRH NOS3 LRP5 IL10 MAPT OLR1 PRL GLP1R GH1 IGF2 CASR ITGB3 IAPP CNR1 CYP2C9 MTHFR DKK1 IL1B ISL1 NFE2L2 REN PAX6 NR3C1 VWF TNFSF11 HP NPY GHR OPRM1 IL18 DPP4 CYP17A1 GAD2 NPPB TLR4 IGFBP2 APOC3 LEPR AR SOD1 BMP6 GAD1 IFNA2 NPPA PCSK9 CD79A ESR1 EPO FOXM1 SST ACHE PIK3CA PRF1 CP APOE BMP4 KLK3 IL2 NEUROD1 IL1R1 FAS SPARC CCL2 C3 AGTR1 HGF PDX1 IGFBP3 IL6 PON1 ALB APP NEUROG3 PTGS1 CPT2 FOXA2 LCAT COMT IGFBP1 APOA4 UCP2 HSPD1 POMC PROC Supplementary Table 2. Involved GO terms from ClueGo enrichment analysis for cluster 1 genes. Group p-Value Corrected with % Associated Nr. GO ID GO Term Associated Genes Found Bonferroni step Genes Genes down [AGT, AGTR1, APLN, APLNR, APP, BDKRB2, C3, CCK, CCKAR, Peptide ligand-binding CCL5, CCR2, CCR5, CX3CR1, CXCL5, CXCL8, CXCR4, EDN1, R-HSA:375276 7.15293E-47 18.42 35.00 receptors EDNRA, F2, GAL, GHSR, GRP, HCRT, KNG1, MLN, NPY, NTS, OPRM1, OXT, POMC, PPY, PYY, SST, TAC1, TRH] [ADORA1, ADRA2A, ADRA2B, AGT, AGTR1, APLN, APLNR, APP, BDKRB2, C3, CCK, CCKAR, CCL5, CCR2, CCR5, CNR1, Class A/1 (Rhodopsin- CNR2, CX3CR1, CXCL5, CXCL8, CXCR4, DRD2, DRD4, EDN1, R-HSA:373076 7.15293E-47 14.81 48.00 like receptors) EDNRA, F2, GAL, GHSR, GNRH1, GPR39, GRP, HCRT, HTR1A, HTR2A, KNG1, MLN, MTNR1A, MTNR1B, NPY, NTS, OPRM1, OXT, POMC, PPY, PYY, SST, TAC1, TRH] [ADORA1, ADRA2A, ADRA2B, AGT, AGTR1, APLN, APLNR, BDKRB2, C3, CCK, CCKAR, CNR1, CNR2, DRD2, DRD4, EDN1, Neuroactive ligand- KEGG:04080 7.15293E-47 12.13 41.00 EDNRA, F2, GAL, GCG, GCGR, GHSR, GNRH1, GRP, HCRT, receptor interaction HTR1A, HTR2A, KNG1, MLN, MTNR1A, MTNR1B, NPY, NTS, OPRM1, OXT, POMC, PPY, PYY, SST, TAC1, TRH] [ADORA1, ADRA2A, ADRA2B, AGT, AGTR1, APLN, APLNR, APP, BDKRB2, C3, CASR, CCK, CCKAR, CCL5, CCR2, CCR5, CNR1, CNR2, CX3CR1, CXCL5, CXCL8, CXCR4, DRD2, DRD4, R-HSA:500792 GPCR ligand binding 7.15293E-47 11.16 51.00 EDN1, EDNRA, F2, GAL, GCG, GCGR, GHSR, GNRH1, GPR39, GRP, HCRT, HTR1A, HTR2A, KNG1, MLN, MTNR1A, MTNR1B, NPY, NTS, OPRM1, OXT, POMC, PPY, PYY, SST, TAC1, TRH] [ADORA1, ADRA2A, ADRA2B, AGT, APLN, APLNR, APOA1, APOA2, APOB, APOE, APP, BDKRB2, C3, CASR, CCL5, CCR2, G alpha (i) signalling R-HSA:418594 7.15293E-47 9.09 37.00 CCR5, CNR1, CNR2, CX3CR1, CXCL5, CXCL8, CXCR4, DRD2, events DRD4, GAL, GNAI1, HTR1A, KNG1, MTNR1A, MTNR1B, NPY, OPRM1, POMC, PPY, PYY, SST] [AHSG, ALB, APOA1, APOA2, APOA5, APOB, APOE, APP, Post-translational protein BMP4, C3, CP, CSF1, CST3, F5, FGA, FGF23, IGFBP1, IGFBP3, R-HSA:8957275 7.24486E-42 28.70 31.00 phosphorylation IGFBP5, IGFBP7, IL6, KNG1, PCSK9, PNPLA2, PROC, SERPINA1, SERPINC1, SPP1, TF, TIMP1, TNC] Regulation of Insulin-like [AHSG, ALB, APOA1, APOA2, APOA5, APOB, APOE, APP, R-HSA:381426 Growth Factor (IGF) 7.24486E-42 25.60 32.00 BMP4, C3, CP, CSF1, CST3, F2, F5, FGA, FGF23, IGFBP1, IGFBP3, transport and uptake by Insulin-like Growth IGFBP5, IGFBP7, IL6, KNG1, PCSK9, PNPLA2, PROC, SERPINA1, Factor Binding Proteins SERPINC1, SPP1, TF, TIMP1, TNC] (IGFBPs) [AGT, AGTR1, APP, BDKRB2, CASR, CCK, CCKAR, EDN1, G alpha (q) signalling EDNRA, F2, GAST, GCG, GCGR, GHSR, GNRH1, GPR39, GRP, R-HSA:416476 6.88134E-26 12.44 27.00 events HCRT, HTR2A, KNG1, MLN, NTS, OXT, PIK3CA, PIK3R1, TAC1, TRH] Adrenaline signalling R-HSA:392023 through Alpha-2 6.72026E-10 66.67 2.00 [ADRA2A, ADRA2B] adrenergic receptor R-HSA:390651 Dopamine receptors 6.72026E-10 40.00 2.00 [DRD2, DRD4] Common Pathway of R-HSA:140875 6.72026E-10 22.73 5.00 [F2, F5, FGA, PROC, SERPINC1] Fibrin Clot Formation R-HSA:390696 Adrenoceptors 6.72026E-10 22.22 2.00 [ADRA2A, ADRA2B] R-HSA:390666 Serotonin receptors 6.72026E-10 16.67 2.00 [HTR1A, HTR2A] Amine ligand-binding R-HSA:375280 6.72026E-10 14.29 6.00 [ADRA2A, ADRA2B, DRD2, DRD4, HTR1A, HTR2A] receptors Platelet Aggregation (Plug R-HSA:76009 6.72026E-10 10.26 4.00 [ADRA2A, ADRA2B, F2, FGA] Formation) Common Pathway of R-HSA:140875 1.1004E-08 22.73 5.00 [F2, F5, FGA, PROC, SERPINC1] Fibrin Clot Formation Transport of gamma- carboxylated protein R-HSA:159763 precursors from the 1.1004E-08 22.22 2.00 [F2, PROC] endoplasmic reticulum to the Golgi apparatus Gamma-carboxylation of R-HSA:159740 1.1004E-08 20.00 2.00 [F2, PROC] protein precursors Removal of aminoterminal R-HSA:159782 1.1004E-08 20.00 2.00 [F2, PROC] propeptides from gamma- carboxylated proteins Intrinsic Pathway of R-HSA:140837 1.1004E-08 18.18 4.00 [F2, KNG1, PROC, SERPINC1] Fibrin Clot Formation Gamma-carboxylation, transport, and amino- R-HSA:159854 1.1004E-08 18.18 2.00 [F2, PROC] terminal cleavage of proteins Formation of Fibrin Clot R-HSA:140877 1.1004E-08 15.38 6.00 [F2, F5, FGA, KNG1, PROC, SERPINC1] (Clotting Cascade) Complement and KEGG:04610 1.1004E-08 11.39 9.00 [BDKRB2, C3, F2, F5, FGA, KNG1, PROC, SERPINA1, SERPINC1] coagulation cascades Platelet Aggregation (Plug R-HSA:76009 1.1004E-08 10.26 4.00 [ADRA2A, ADRA2B, F2, FGA] Formation) Binding and entry of HIV R-HSA:173107 2.31219E-08 20.00 2.00 [CCR5, CXCR4] virion R-HSA:6783783 Interleukin-10 signaling 2.31219E-08 14.89 7.00 [CCL5, CCR2, CCR5, CSF1, CXCL8, IL6, TIMP1] Chemokine receptors R-HSA:380108 2.31219E-08 14.58 7.00 [CCL5, CCR2, CCR5, CX3CR1, CXCL5, CXCL8, CXCR4] bind chemokines Early Phase of HIV Life R-HSA:162594 2.31219E-08 10.00 2.00 [CCR5, CXCR4] Cycle Chagas disease (American KEGG:05142 3.50978E-07 8.74 9.00 [BDKRB2, C3, CCL5, CXCL8, GNAI1, IL6, KNG1, PIK3CA, PIK3R1] trypanosomiasis) KEGG:04614 Renin-angiotensin system 0.000272724 8.70 2.00 [AGT, AGTR1] KEGG:04924 Renin secretion 0.000272724 8.70 6.00 [ADORA1, AGT, AGTR1, EDN1, EDNRA, GNAI1] R-HSA:8963901 Chylomicron remodeling 0.000437865 55.56 5.00 [APOA1, APOA2, APOA5, APOB, APOE] R-HSA:8963888 Chylomicron assembly 0.000437865 44.44 4.00 [APOA1, APOA2, APOB, APOE] R-HSA:8964026 Chylomicron clearance 0.000437865 40.00 2.00 [APOB, APOE] Scavenging by Class B R-HSA:3000471 0.000437865 33.33 2.00 [APOA1, APOB] Receptors R-HSA:8964058 HDL remodeling 0.000437865 30.00 3.00 [ALB, APOA1, APOE] Plasma lipoprotein R-HSA:8963898 0.000437865 22.22 4.00 [APOA1, APOA2, APOB, APOE] assembly Plasma lipoprotein R-HSA:8963899 0.000437865 20.00 6.00 [ALB, APOA1, APOA2, APOA5, APOB, APOE] remodeling Scavenging by Class A R-HSA:3000480 0.000437865 15.79 3.00 [APOA1, APOB, APOE] Receptors Scavenging of heme from R-HSA:2168880 0.000437865 15.38 2.00 [ALB, APOA1] plasma Plasma lipoprotein R-HSA:8964043 0.000437865 12.12 4.00 [APOA1, APOB, APOE, PCSK9] clearance Regulation of TLR by R-HSA:5686938 0.000437865 10.53 2.00 [APOB, FGA] endogenous ligand R-HSA:8964038 LDL clearance 0.000437865 10.53 2.00 [APOB, PCSK9] Plasma lipoprotein R-HSA:174824 assembly, remodeling, and 0.000437865 10.14 7.00 [ALB, APOA1, APOA2, APOA5, APOB, APOE, PCSK9] clearance KEGG:04979 Cholesterol metabolism 0.000437865 10.00 5.00 [APOA1, APOA2, APOB, APOE, PCSK9] Binding and Uptake of R-HSA:2173782 Ligands by Scavenger 0.000437865 9.52 4.00 [ALB, APOA1, APOB, APOE] Receptors Retinoid metabolism and R-HSA:975634 0.000437865 9.30 4.00 [APOA1, APOA2, APOB, APOE] transport Metabolism of fat-soluble R-HSA:6806667 0.000437865 8.51 4.00 [APOA1, APOA2, APOB, APOE] vitamins Vitamin digestion and KEGG:04977 0.000437865 8.33 2.00 [APOA1, APOB] absorption MET activates R-HSA:8851907 0.004786962 33.33 2.00 [PIK3CA, PIK3R1] PI3K/AKT signaling Activated NTRK3 signals R-HSA:9603381 0.004786962 33.33 2.00 [PIK3CA, PIK3R1] through PI3K Activated NTRK2 signals R-HSA:9028335 0.004786962 28.57 2.00 [PIK3CA, PIK3R1] through PI3K R-HSA:198203 PI3K/AKT activation 0.004786962 22.22 2.00 [PIK3CA, PIK3R1] PI3K events in ERBB4 R-HSA:1250342 0.004786962 20.00 2.00 [PIK3CA, PIK3R1] signaling Signaling by FGFR3 R-HSA:8853334 0.004786962 20.00 2.00 [PIK3CA, PIK3R1] fusions in cancer Signaling by FGFR4 in R-HSA:5655291 0.004786962 18.18 2.00 [PIK3CA, PIK3R1] disease R-HSA:5654710 PI-3K cascade:FGFR3 0.004786962 16.67 3.00 [FGF23, PIK3CA, PIK3R1] Erythropoietin activates R-HSA:9027276 Phosphoinositide-3- 0.004786962 16.67 2.00 [PIK3CA, PIK3R1] kinase (PI3K) R-HSA:5654720 PI-3K cascade:FGFR4 0.004786962 15.00 3.00 [FGF23, PIK3CA, PIK3R1] R-HSA:5654689 PI-3K cascade:FGFR1 0.004786962 14.29 3.00 [FGF23, PIK3CA, PIK3R1] Signaling by FGFR3 in R-HSA:5655332 0.004786962 13.64 3.00 [FGF23, PIK3CA, PIK3R1] disease Signaling by FGFR3 point R-HSA:8853338 0.004786962 13.64 3.00 [FGF23, PIK3CA, PIK3R1] mutants in cancer Constitutive Signaling by R-HSA:5637810 0.004786962 13.33 2.00 [PIK3CA, PIK3R1] EGFRvIII Signaling by EGFRvIII in R-HSA:5637812 0.004786962 13.33 2.00 [PIK3CA, PIK3R1] Cancer R-HSA:5654695 PI-3K cascade:FGFR2 0.004786962 13.04 3.00 [FGF23, PIK3CA, PIK3R1] PI3K events in ERBB2 R-HSA:1963642 0.004786962 12.50 2.00 [PIK3CA, PIK3R1] signaling Role of R-HSA:2730905 LAT2/NTAL/LAB on 0.004786962 12.50 2.00 [PIK3CA, PIK3R1]
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  • The Role of Pik3r1 in the Regulation of Adipose Tissue Insulin

    The Role of Pik3r1 in the Regulation of Adipose Tissue Insulin

    THE ROLE OF PIK3R1 IN THE REGULATION OF ADIPOSE TISSUE INSULIN SENSITIVITY by ZACHARY STEPHEN CLAYTON A DISSERTATION Presented to the Department of Human Physiology and the Graduate School of the University of Oregon in partial fulfillment of the requirements for the degree of Doctor of Philosophy June 2018 DISSERTATION APPROVAL PAGE Student: Zachary Stephen Clayton Title: The Role of Pik3r1 in the Regulation of Adipose Tissue Insulin Sensitivity This dissertation has been accepted and approved in partial fulfillment of the requirements for the Doctor of Philosophy degree in the Department of Human Physiology by: Carrie E. McCurdy, PhD Advisor John R. Halliwill, PhD Core Member Hans C. Dreyer, PhD Core Member Annie Zemper, PhD Institutional Representative and Sara D. Hodges Interim Vice Provost and Dean of the Graduate School Original approval signatures are on file with the University of Oregon Graduate School. Degree awarded June 2018. ii © 2018 Zachary Stephen Clayton iii DISSERTATION ABSTRACT Zachary Stephen Clayton Doctor of Philosophy Department of Human Physiology June 2018 Title: The Role of Pik3r1 in the Regulation of Adipose Tissue Insulin Sensitivity Obesity is a burgeoning health crisis in the United States. Obesity is associated with an earlier and greater risk for developing metabolic diseases. Insulin resistance is a central and defining feature of the metabolic diseases associated with obesity. Class 1a Phosphatidylinositol 3-kinase (PI3K) is integral in canonical insulin signaling. PI3K contains regulatory (p85a/b, p55a/g, p50a) and catalytic (p110a/b/d) subunits. The a regulatory subunits are encoded by Pik3r1. Increased Pik3r1 abundance has been observed in obese white adipose tissue (WAT).
  • Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation

    Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation

    Page 1 of 44 Diabetes Pik3r1 is Required for Glucocorticoid-induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis Taiyi Kuo1, 3+, Tzu-Chieh Chen2,3+, Rebecca A. Lee1,3, Nguyen Huynh Thao Nguyen3, Augusta E 3 3 1, 2, 3* Broughton , Danyun Zhang , and Jen-Chywan Wang Endocrinology Graduate Program1, Metabolic Biology Graduate Program2 and Department of Nutritional Sciences & Toxicology3, University of California Berkeley, Berkeley, CA 94720- 3104 + These authors contributed equally to this work *Corresponding author: Jen-Chywan Wang, 315 Morgan Hall, UC Berkeley, Berkeley, CA 94720-3104, email: [email protected], Phone: 510-643-1039 Running Title: Pik3r1 and glucocorticoid-induced adipocyte lipolysis Keywords: Glucocorticoids, Glucocorticoid Receptor, Lipolysis, Pik3r1, Perilipin 1, Protein Kinase A 1 Diabetes Publish Ahead of Print, published online March 14, 2017 Diabetes Page 2 of 44 Abstract Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, while superfluous lipolysis causes metabolic disorders, including dyslipidemia and hepatic steatosis. Glucocorticoid-induced lipolysis requires the phosphorylation of cytosolic hormone sensitive lipase (HSL) and perilipin 1 (Plin1) in the lipid droplet by protein kinase A (PKA). We previously identified Pik3r1 (a.k.a. p85α) as a glucocorticoid receptor target gene. Here, we found that glucocorticoids increased HSL phosphorylation, but not Plin1 phosphorylation, in adipose tissue-specific Pik3r1-null (AKO) mice. Furthermore, in lipid droplets, the phosphorylation of HSL and Plin1 and the levels of catalytic and regulatory subunits of PKA were increased by glucocorticoids in wild type mice. However, these effects were attenuated in AKO mice. In agreement with reduced WAT lipolysis, glucocorticoid- initiated hepatic steatosis and hypertriglyceridemia were improved in AKO mice.
  • Integrative Kinome Profiling Identifies Mtorc1/2 Inhibition As Treatment Strategy in Ovarian Clear Cell Carcinoma

    Integrative Kinome Profiling Identifies Mtorc1/2 Inhibition As Treatment Strategy in Ovarian Clear Cell Carcinoma

    Published OnlineFirst April 23, 2018; DOI: 10.1158/1078-0432.CCR-17-3060 Cancer Therapy: Preclinical Clinical Cancer Research Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma Joseph J. Caumanns1, Katrien Berns2, G. Bea A. Wisman1, Rudolf S.N. Fehrmann3, Tushar Tomar1, Harry Klip1, Gert J. Meersma1, E. Marielle Hijmans2, Annemiek M.C. Gennissen2, Evelien W. Duiker4, Desiree Weening5, Hiroaki Itamochi6, Roelof J.C. Kluin2, Anna K.L. Reyners3, Michael J. Birrer7, Helga B. Salvesen8, Ignace Vergote9, Els van Nieuwenhuysen9, James Brenton10, E. Ioana Braicu11, Jolanta Kupryjanczyk12, Beata Spiewankiewicz13, Lorenza Mittempergher2, Rene Bernards2, Ate G.J. van der Zee1, and Steven de Jong3 Abstract Purpose: Advanced-stage ovarian clear cell carcinoma Results: We identified several putative driver mutations in (OCCC) is unresponsive to conventional platinum-based che- kinases at low frequency that were not previously annotated in motherapy. Frequent alterations in OCCC include deleterious OCCC. Combining mutations and copy-number alterations, 91% mutations in the tumor suppressor ARID1A and activating of all tumors are affected in the PI3K/AKT/mTOR pathway, mutations in the PI3K subunit PIK3CA.Inthisstudy,weaimed the MAPK pathway, or the ERBB family of receptor tyrosine to identify currently unknown mutated kinases in patients with kinases, and 82% in the DNA repair pathway. Strong p-S6 staining OCCC and test druggability of downstream affected pathways in patients with OCCC suggests high mTORC1/2 activity. We in OCCC models. consistently found that the majority of OCCC cell lines are Experimental Design: In a large set of patients with OCCC (n ¼ especially sensitive to mTORC1/2 inhibition by AZD8055 and 124), the human kinome (518 kinases) and additional cancer- not toward drugs targeting ERBB family of receptor tyrosine related genes were sequenced, and copy-number alterations were kinases or DNA repair signaling.
  • Attenuated Pik3r1 Expression Prevents Insulin Resistance and Adipose Tissue Macrophage Accumulation in Diet-Induced Obese Mice Carrie E

    Attenuated Pik3r1 Expression Prevents Insulin Resistance and Adipose Tissue Macrophage Accumulation in Diet-Induced Obese Mice Carrie E

    ORIGINAL ARTICLE Attenuated Pik3r1 Expression Prevents Insulin Resistance and Adipose Tissue Macrophage Accumulation in Diet-Induced Obese Mice Carrie E. McCurdy,1,2,3 Simon Schenk,4 Michael J. Holliday,1,2,3 Andrew Philp,5 Julie A. Houck,1,2,3 David Patsouris,6 Paul S. MacLean,2 Susan M. Majka,2,3 Dwight J. Klemm,2,3 and Jacob E. Friedman1,7 Obese white adipose tissue (AT) is characterized by large-scale inhibitor of kappa B kinase b (IKKb)andJunNH2-terminal infiltration of proinflammatory macrophages, in parallel with sys- kinase (JNK), which impinge upon the insulin signaling temic insulin resistance; however, the cellular stimulus that cascade by inhibiting tyrosine phosphorylation of insulin initiates this signaling cascade and chemokine release is still receptor substrate 1 (IRS1), leading to impaired insulin unknown. The objective of this study was to determine the role of activation of phosphoinositide 3-kinase (PI3K) and Akt (1). the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT The chemoattractant stimulus and the molecular details fi fi macrophage (ATM) in ltration in obesity. Here, we nd that the underlying cross-talk between infiltrating macrophage and Pik3r1 regulatory subunits (i.e., p85a/p55a/p50a) are highly in- duced in AT from high-fat diet–fed obese mice, concurrent with the adipocyte is an area of intense investigation. Envi- insulin resistance. Global heterozygous deletion of the Pik3r1 reg- ronmental cues including adipose tissue (AT) hypoxia, cell ulatory subunits (aHZ), but not knockout of Pik3r2 (p85b), pre- death, physical stress on adipocyte extracellular matrix, serves whole-body, AT, and skeletal muscle insulin sensitivity, and increased lipolysis have all been identified as mecha- despite severe obesity.
  • Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma

    Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma

    cancers Article Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma and to Provide New Insights into Intrinsic and Acquired Mechanism of Resistance 1, , 2, 1 3 Mohamad Krayem * y , Philippe Aftimos y, Ahmad Najem , Tim van den Hooven , Adriënne van den Berg 3, Liesbeth Hovestad-Bijl 3, Rik de Wijn 3, Riet Hilhorst 3 , Rob Ruijtenbeek 3, Malak Sabbah 1, Joseph Kerger 2, Ahmad Awada 1,2 , Fabrice Journe 1 and Ghanem E. Ghanem 1 1 Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; [email protected] (A.N.); [email protected] (M.S.); [email protected] (A.A.); [email protected] (F.J.); [email protected] (G.E.G.) 2 Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; [email protected] (P.A.); [email protected] (J.K.) 3 PamGene International BV, 5211HH ’s-Hertogenbosch, The Netherlands; [email protected] (T.v.d.H.); [email protected] (A.v.d.B.); [email protected] (L.H.-B.); [email protected] (R.d.W.); [email protected] (R.H.); [email protected] (R.R.) * Correspondence: [email protected] Both authors equally contributed to this manuscript. y Received: 20 January 2020; Accepted: 20 February 2020; Published: 22 February 2020 Abstract: Mitogen-activated protein kinase (MAPK) inhibition with the combination of BRAF (Rapidly Accelerated Fibrosarcoma) and MEK (Mitogen-activated protein kinase kinase) inhibitors has become the standard of first-line therapy of metastatic melanoma harbouring BRAF V600 mutations. However, about half of the patients present with primary resistance while the remaining develop secondary resistance under prolonged treatment.